tbuckley/cabot-search huggingface dataset:
Microsatellite instability (MSI), mismatch repair (MMR), and tumor mutational burden (TMB) as predictive biomarkers for immune checkpoint inhibitor (ICI) effectiveness in real-world patients with metastatic colorectal cancer (mCRC).
Authors: Haley Ellis, Samuel J Klempner, Julia C. F. C. F. Quintanilha, Parvathi Myer, Douglas I. Lin, Nicole Panarelli, Virginia Fisher, Gerald Li, Richard S.P. Huang, Jeffrey S. Ross, Geoffrey R. Oxnard, Ryon Graf
Journal: Journal of Clinical Oncology (2023)

46 Background: The KEYNOTE-177 randomized controlled trial demonstrated that mCRC patients with MSI high (MSI-H) and/or deficient MMR (dMMR) have better outcomes on first-line ICI than chemotherapy. This study aimed to evaluate MSI by next-generation sequencing (NGS) as a predictive biomarker of ICI effectiveness in real-world settings, and compare MSI (NGS), dMMR (immunohistochemistry, IHC), and TMB (10 mut/Mb cutoff) in predicting ICI outcomes. Methods: A prospectively declared statistical analysis plan compared the effectiveness of first-line treatment ICI versus chemotherapy in patients with MSI-H mCRC, and compared the predictive power of ICI outcomes associated with biomarkers in any line of therapy (LOT). Patient data was obtained by the US-based de-identified Flatiron Health-Foundation Medicine real-world mCRC clinico-genomic database (FH-FMI CGDB), originating from ~280 US cancer clinics between Jan/2011 and Dec/2021. Differences in progression-free survival (PFS) and overall survival (OS) were evaluated by Cox proportional hazard models, adjusted for a risk score generated from prognostic clinical features. The likelihood ratio test evaluated the superiority of a biomarker in anticipating outcomes. Results: Patients with MSI-H mCRC had more favorable outcomes receiving first-line ICI (n=49) than chemotherapy (n=89) for PFS (median 24.87 vs. 5.65 months, hazard ratio (HR): 0.31, 95% confidence interval (CI) 0.18-0.52, p &lt;0.0001) and OS (median not reached (NR) vs. 24.1 months, HR: 0.45, 95% CI 0.23-0.88, p = 0.02). mCRC patients receiving ICI in any LOT (n=182) had favorable outcomes when MSI-H, dMMR, or TMB ≥10 (all p &lt;0.001). MSI (NGS) and MMR (IHC) were 90% concordant. MSI reclassified six cases that were proficient (p)MMR (all with TMB &gt;10, three with mutations in MMR genes, and 5 with BRAF mutation, consistent with MSI biology). When MSI (NGS) is added to dMMR (IHC) evaluation, there is an improvement in the prediction of TTNT (p = 0.0013), PFS (p = 0.0202), and OS (p = 0.0717), but adding MMR status to MSI did not improve explanatory power. Conclusions: MSI (NGS) robustly identifies mCRC patients with favorable outcomes on first-line ICI vs. chemotherapy, and is a nominally better predictor of ICI outcomes when compared with dMMR (IHC) alone. dMMR (IHC), MSI (NGS), and TMB have similar predictive power for ICI benefit. [Table: see text]
Trial in progress: Natural killer (NK) cells with TGFβ receptor I inhibitor vactosertib and IL-2 in patients with metastatic colorectal cancer or hematologic malignancies.
Authors: J. Eva Selfridge, David L Bajor, Amr Mohamed, Sakti Chakrabarti, Jane Reese, Hillard M. Lazarus, Afshin Dowlati, Amit Mahipal, David Wald
Journal: Journal of Clinical Oncology (2023)

TPS273 Background: Natural killer (NK) cell therapy is emerging as a promising therapy for patients (pts) with solid tumors and hematologic malignancies with no reported toxicity associated with the cell therapy product itself. NK cell trials in solid tumors are limited by immune inhibitory tumor microenvironments that prevent trafficking and activity of donor NK cells, which is largely governed by TGFβ signaling. We recently developed a novel platform for ex vivo expansion of healthy donor NK cells. We previously showed these cells to be safe in a dose-escalation study when given without cytokine support, with early evidence of response in pts with metastatic colorectal cancer (CRC) and in pts with hematologic malignancies. IL-2 has been well-established as an important activating cytokine supporting NK cells in humans, but can also induce regulatory T cells, which further suppress NK cells by producing TGFβ. We seek to improve upon the early activity we previously observed with NK cells alone by administering concurrently with IL-2 and by limiting the inhibitory tumor microenvironment and regulatory T cells with TGFβ receptor 1 inhibitor vactosertib. Methods: This phase Ib open-label study evaluates the safety and persistence (primary objectives), and the clinical and biological activity and trafficking (secondary objectives) of our novel NK cell therapy in combination with IL-2 (aldesleukin) and TGFβ receptor 1 inhibitor vactosertib. Up to 12 pts with metastatic CRC or relapsed/refractory hematologic malignancies will be enrolled. Pts will undergo low-dose lymphodepletion with fludarabine and cyclophosphamide followed by 2 infusions of NK cells, administered 14 days apart. Concurrently, pts will receive aldesleukin subcutaneously 3 times weekly and vactosertib orally 5 consecutive days/week x4 weeks total. Pts will undergo pre- and post-treatment biopsies for quantification of NK cell trafficking and exploration of immune cell profiling changes in the tumor microenvironment. The trial is currently open to enrollment, with 1 pt accrued at time of submission. Clinical trial information: NCT05400122 .
The role of socioeconomic deprivation in gastrointestinal cancer clinical trial enrollment at an NCI-designated comprehensive cancer center.
Authors: Daniel Strebig, Taymeyah E. Al-Toubah, Emily Coughlin, Rahul Mhaskar, Sylea Lowery, Ebin Mathew, Mitchell Capelli, Aishwarya Pattnaik, Kea Turner, Kedar Kirtane, Amina Dhahri, Richard D. Kim, Jennifer B. Permuth, Susan Thomas Vadaparampil, Jason B. Fleming, Jonathan R. Strosberg, Benjamin Daniel Powers
Journal: Journal of Clinical Oncology (2023)

785 Background: Socioeconomic deprivation has been described as a barrier to cancer clinical trial participation. However, few studies have examined socioeconomic deprivation using patient-level or granular geocoded designations. To overcome this challenge, the Area Deprivation Index (ADI) was used to assess neighborhood socioeconomic deprivation in a cohort of gastrointestinal cancer clinical trial patients at an NCI-Designated Comprehensive Cancer Center. Methods: Patients enrolled in a gastrointestinal cancer clinical trial from 2008 to 2019 with an identifiable ADI national rank were identified. Socioeconomic deprivation was assessed using the ADI, a publicly available, validated dataset that ranks census block groups into percentiles using variables such as income, education, employment, and housing characteristics. For this study, ADI was categorized as quintiles listed in the table. Statistical analyses included Chi-square and Kruskal-Wallis tests. Results: The median age of the cohort (N=1,334) was 62.0 years. Most patients were male (54.3%). Race included White (88.2%), African American (6.8%), and Asian (1.5%) patients. Hispanic/Latinx patients made up 6.7% of the cohort. The median ADI was 46. The proportion of enrollees from lowest to highest ADI quintile was 11.2%, 29.3%, 27.3%, 19.1%, and 13.1%. Trial enrollment differed by ADI and age (p=0.019), gender (p=0.042), race (p&lt;0.001), and insurance (p=0.001). Conclusions: In this study, patients enrolled in gastrointestinal cancer clinical trials had lower neighborhood socioeconomic deprivation than the national or state average. African American, Hispanic/Latinx, female, and uninsured patients comprised a lower proportion of enrollees compared to catchment area estimates (10.6%, 17.7%, 51.3%, and 12.4%, respectively). These findings suggest inequity in clinical trial enrollment and warrant further studies to identify drivers of these disparities. [Table: see text]
Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer.
Authors: Chengwei Peng, Saad Saffo, Michael Shusterman, Daniel Jacob Becker, Jordan Berlin, Paul Eliezer Oberstein, Anil Nagar, Shun Yu
Journal: Journal of Clinical Oncology (2023)

59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p &lt; 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were &gt; 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.
Comparison of survival between de novo stage IV and recurrent stage IV gastric cancer.
Authors: Jun Ho Ji, Danbi Lee, Yong-Pyo Lee, Seok Jae Huh, Se-Il Go, Jung Hoon Kim, Sung Yong Oh, Jung Hun Kang, Kwang Min Kim
Journal: Journal of Clinical Oncology (2023)

304 Background: The characteristics and prognosis of de novo metastatic gastric cancer and recurrent metastatic gastric cancer have not yet been elucidated. Here, we compare prognosis and characteristics of patients with de novo versus recurrent gastric cancer. Methods: This retrospective study included 301 advanced pathologically confirmed gastric cancer patients who received palliative chemotherapy between 2012 and 2022. The de novo cohort was included of patients who presented with distant metastasis at diagnosis and recurrent metastatic cohort was composed of patients with metastasis after curative gastrectomy. We analyzed prognostic association by Cox regression and compared survival time of both cohorts using the Kaplan-meire method. Results: A total of 167 de novo and 112 recurrent patients were included. There were no differences noted among the patients with de novo disease and recurrent metastatic disease with respect to age, sex, ECOG, primary cancer location and pathologic features. Patients in the recurrent group versus de novo group were longer duration of chemotherapy (1.16 ± 1.18 years versus 0.85 ± 0.84, P = 0.01) and lower mean body mass index. (20.22 ± 2.78 versus 21.93 ± 3.38, p &lt; 0.001) The median overall survival in the de novo group was 11.6 versus s 14.4 months in the recurrent group. ( P = 0.02) In a multivariate analysis, the age of 70 years or older at the time of stage 4 diagnosis was independently associated with shorter survival. Conclusions: De novo and recurrent metastatic gastric cancer characterize distinguished subpopulations. And advanced gastric cancer with distant recurrence has significantly better survival versus those with de novo cohort. This differences between de novo and recurrent gastric cancer could facilitate discussions about patient selection of clinical trial and help with advanced personalized treatment. [Table: see text]
Real-world assessment of treatment sequencing of patients with advanced biliary tract cancer in a private practice in Rio de Janeiro and São Paulo, Brazil.
Authors: Ligia Carvalho, Kaique Ferreira Costa de Almeida, Lais Saldanha, Kelly de Paula Beck, Ana Paula Victorino
Journal: Journal of Clinical Oncology (2023)

587 Background: Biliary tract cancer, including cholangiocarcinoma and gallbladder carcinoma, have low incidence and poor prognosis. Despite representing a heterogeneous group, the studies encompass these malignancies as the same entity. There are few phase III trials that evaluate treatment sequencing in the metastatic setting. The ABC 02 trial showed an increase in overall survival (OS) with Gemcitabine and Cisplatin (GemCis) in first line and the ABC 06 trial an increase in OS in second-line Folfox. Recently, the TOPAZ 1 trial demonstrated benefit of first-line immunotherapy. The primary objective of this study was OS in patients with advanced cholangiocarcinoma according to treatment. The secondary objective was to analyze the patients characteristics. Methods: Retrospective analysis of medical records from two private institutions. Patients were eligible if they had advanced intra or extra cholangiocarcinoma or gallbladder carcinoma, undergoing chemotherapy from January of 2015 to January of 2021. Results: Database included 82 patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma or gallbladder carcinoma, 54%, 23% and 23%, respectively. Median age was 65 years old, with an equal proportion between sexes. 75% had metastasis at diagnosis and 12 patients (14%) underwent more than two lines of treatment. Median OS was 288 days. GemCis was the most common first line protocol (62%), followed by Gemcitabine and Oxaliplatin (17%). There was no difference in OS between the regimens, regardless of the primary site. Folfiri and Folfox were used in the same proportion in second line (17% for each), but with a significant increase in OS for Folfiri (485 days vs. 368 days, p=0.02), regardless of the primary site. According to univariate analysis of factors associated with mortality, the significant variables were: surgery for primary site (HR 0.49 [95% CI 0.28-0.85]; p=0.01), metastasis at diagnosis (HR 1.89 [95% CI 1.10-3.25]; p=0.02), liver metastasis at diagnosis (HR 1.69 [95% CI 1.02-2.80]; p=0.04), and more than two lines of treatment (HR 0.41 [95% CI 0.21-0.80]; p=0.009). Conclusions: Despite being retrospective and not using first-line immunotherapy, this study was able to demonstrate no difference in OS between first-line regimens with GemCis or Gemcitabine and Oxaliplatin. However, when analyzing second-line sequencing, Folfiri demonstrated benefit independent of the primary site.
Real-world use of biologics and its association with outcomes in RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) in Canada.
Authors: Winson Y. Cheung, Devon J. Boyne, Darren R. Brenner, Daniel Martinez, Rajvi J. Wani, Elaine Ngan
Journal: Journal of Clinical Oncology (2023)

56 Background: The use of biologics in combination with chemotherapy early in the course of treatment in mCRC improves outcomes, but whether this approach is uniformly adopted in clinical practice is unclear. This study aims to describe biomarker testing, treatment patterns, and survival of RAS WT, left-sided mCRC patients in a real-world population. Methods: We performed deterministic linkages with population-based data sources, including the cancer registry, pharmacy data, electronic medical records, and vital statistics to identify all patients who were diagnosed with RAS WT, left-sided mCRC, and treated with first-line (1L) combination systemic therapy from 2014 to 2019 in Alberta, Canada. Patients were followed until December 31, 2020. Results: Of 2,721 patients with left-sided mCRC, 1,375 were referred and received systemic therapy, 977 underwent RAS testing prior to or within 30 days of initiating 1L treatment, and 420 were found to be RAS WT. Among them, 320 were treated with 1L combination systemic therapy: FOLFOX/CAPOX/FOLFIRI (n=204), panitumumab (pani) with doublet chemotherapy (n=64), or bevacizumab (bev) with doublet chemotherapy (n=52). The interval from diagnosis to RAS test results was 38 (IQR 24-61) days. Only 207 (65%) and 125 (39%) of the 320 1L-treated patients reached 2L and 3L therapy, respectively. Median overall survival based on the different 1L regimens are summarized. Conclusions: Many real-world patients with mCRC were not exposed to biologics as part of their front-line treatment. There is a need to enhance RAS testing in 1L as 29% of patients were not tested, despite recommendations from guidelines. Because attrition across lines of therapy is high in mCRC, the opportunity to receive and benefit from biologics in later lines of therapy may be importantly reduced. [Table: see text]
Clinical outcomes and barriers to cancer care delivery for patients with rectal cancer in Nairobi, Kenya.
Authors: Dulcie Wanda, Kenneth Merrell, Daniel Ojuka, Joel Omundi Okumu, Primus Ochieng
Journal: Journal of Clinical Oncology (2023)

17 Background: Rectal cancer is among the top ten cancers in Kenya with most patients presenting with locally advanced rectal cancer (LARC). Management requires multimodality treatment including neo-adjuvant therapy and surgery. There is limited data on the outcome for patients with LARC from Kenya and the broader region. The aim of our study was to evaluate outcomes of LARC from a tertiary hospital in Nairobi, Kenya, to identify barriers to care and methods to improve cancer outcomes. Methods: We conducted a retrospective study of patients with LARC treated at the Kenyatta National Hospital between January 2016 and January 2020. Patients with histologic confirmation of rectal cancer, received neo-adjuvant treatment, and had available survival data in the electronic medical record were included in the analysis. A data abstraction tool was used to collect patient demographics and cancer outcomes including age, gender, tumor stage, cancer and vital status. Overall and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 182 patients were identified that met inclusion on the study. The median age of 53 years (range, 21 - 82) years, 52.5% were female and 94.5% had cT3 (57.5%) or cT4 (37%) disease and 75% of patients had N+ disease. The time from symptoms onset to diagnosis and diagnosis date to treatment was 14 and 3.6 months, respectively. months76% of patients were from rural regions of Kenya. Most patients (95%) received long-course chemoradiation (50.4 Gy/28 fractions) with concurrent Capecitabine 825 mg/m2 chemotherapy. Only 5% (n=9) of patients had resection after neoadjuvant therapy. The median progression free and overall survival after neo-adjuvant treatment respectively was 24 months (IQR: 23 – 25 months) and 36 months (IQR: 24 – 36 months), respectively. Presence of comorbidities (OR =7.87, 95% CI: 3.46 – 17.89, p&lt;0.001), tumor staging cT3 (OR = 2.34, 95% CI: 1.13 – 7.49, p =0.013), tumor staging cT4 (OR =4.02, 95% CI: 2.12 – 10.34, p =0.004) and increase in duration of symptoms by one month (OR =1.04, 95% CI: 1.01 – 2.14, p =0.003) were significantly associated with lower overall survival. Conclusions: Our results represent one of the largest series of outcomes for rectal cancer from Sub-Saharan Africa and serves as a baseline for clinical improvement. The long interval from symptom onset to diagnosis represents an area for patient intervention and development of screening protocols. Further exploration into the barriers that limit access to surgery is warranted and development of a non-operative protocol may serve the patient population due to the limited capacity of surgery.
Use of positron emission tomography-computed tomography (PET-CT) scan in patients with gastrointestinal (GI) cancer at the University Hospital of Montreal (CHUM).
Authors: Ahmad Gebai, Carlos Enrique Melendez Pena, Francine Aubin, Jean-Pierre M. Ayoub, Danielle Charpentier, Mustapha Tehfe
Journal: Journal of Clinical Oncology (2023)

793 Background: In the province of Quebec, Canada, PET-CT scan recommendations are published by the Institut national d’excellence en santé et en services sociaux (INESSS). These recommendations are based on evidence-based literature and publications from oncology societies (ASCO, NCCN...) Judicious use of PET-CT scans is particularly important in a public health system for appropriate allocation of resources. An analysis conducted by INESSS in 2017 demonstrated a remarkable use of 507 PET-CT scans per 100,000 persons in Quebec, an incidence more than twice as high as other provinces, and equivalent to that of the United States (510 per 100,000 person). Methods: We present a retrospective quality control study in which all PET-CT scans completed for oncologic purposes for patients of 18 years or older at CHUM between September 1 st and November 30 th , 2019, were included. Patients who had a PET-CT scan for non-oncologic purposes or weren’t followed at the CHUM were excluded. We reviewed disease characteristics of patients, and adherence to 2017 INESSS guidelines. All cancer types were analysed and classified according to imaging reason (staging, response to treatment, follow up). We herein report the use of PET-CT in GI cancers and how it compares to INESSS recommendation . Results: A total of 2331 PET-CT scans were completed in the studied period. Among them 975 PET-CT scans fit our inclusion criteria. 155 patients (16%) underwent PET-CT scans for GI cancers. Only 35% followed INESSS recommendations, 44% did not, and 21% had GI cancer types without revised clear recommendations from INESSS. Among specialists, surgeons requested most PET-CT scans (66%), but surgeons, oncologists, and gastroenterologist were equally non-adherent to guidelines (44, 45, and 43% respectively). Strikingly, 43% of PET-CT scans for GI cancers were prescribed for cancer follow up, yet 83% did not follow guidelines. Most PET-CT scans were used for colorectal (41%) or gastroesophageal cancers (28%), and only 40 and 53% followed guidelines, respectively. 49.7% of PET-CT scans did not result in treatment modification. Conclusions: In our university hospital, more than 40% of PET-CT scans prescribed don’t follow INESSS recommendations. In the interest of proper resource allocation in a public health care system, we recommend guideline adherence and discussion in multidisciplinary Tumour Boards prior to off-label use of PET-CT scans.